Showing posts with label high risk. Show all posts
Showing posts with label high risk. Show all posts

Thursday, January 28, 2021

Dose Painting: simultaneous integrated boost (SIB) to the dominant intraprostatic lesion (DIL)

Two technologies have come together to allow for a new kind of radiation treatment known as simultaneous integrated boost (SIB), or, more informally, “dose painting.” The two technologies are: 
  1. improved imaging by multiparametric MRIs that can more precisely locate tumors within the prostate, and 
  2. improved external beam technology that can deliver doses with submillimeter accuracy. 
Dose painting can be achieved with brachytherapy as well. But just because it can be done, doesn’t mean it should be done. That is, the following two questions must be answered:
  1. Is there any benefit in terms of oncological outcomes?
  2. Is there any increase in treatment toxicity attributable to it?
The arguments for dose painting include:
  • There is often a dominant intraprostatic lesion (DIL) or index tumor. There is some evidence that cancer spreads via clones from it. Because such tumors are often large and high grade, some think that the index tumor may be relatively radioresistant, perhaps because of hypoxia or cancer stem cells. Therefore, a higher dose of radiation may be necessary to kill its cancer cells.
  • By concentrating the radiation’s killing power at the DIL, it may be possible to reduce the radiation dose where it is less needed, and thus spare organs at risk (e.g., bladder and rectum).
The arguments against dose painting include:
  • The index tumor hypothesis is far from proven. In fact, prostate cancer is multifocal in about 80% of men. Reducing the dose elsewhere is risky because cancer cells may survive and propagate.
  • If the dose needed to kill the cancer cells is inadequate, why not increase the dose throughout the prostate to a dose that is adequate? With today’s pinpoint technology, the clinical target volume (the prostate) can be defined with sub-millimeter accuracy and near-perfect shaping.
  • Using mpMRI to precisely delineate the DIL may miss much of it. In fact, a study at UCLA found that tumors delineated by mpMRI missed 80% of the tumor's actual volume.
  • While mpMRI is good at finding large high-grade tumors, sometimes the highest grade tumor is not large, and mpMRI cannot locate it.
  • Intense foci of radiation may increase the probability of normal tissue complications, including damage to the urethra, bladder neck, sphincter, rectum and bowel.
With all these pros and cons in mind, the FLAME randomized clinical trial was instituted to determine whether dose painting is effective and safe in real-world application. Kerkmeijer et al. reported the results of 571 patients treated at 4 institutions in Belgium and the Netherlands from 2009 to 2015. Patients were:
  • Predominantly (85%) high risk
  • Adjuvant ADT was given to 65% for a median of 18 months.
  • Received hypofractionated radiation to the prostate: 77 Gy in 35 treatments, which is biologically equivalent to 82 Gy in 41 treatments.
  • Half received a SIB to the DIL as well: 95 Gy in 35 treatments, which is biologically equivalent to 116 Gy in 58 treatments.
  • The boost dose was reduced sometimes to meet very tight dose constraints on organs at risk.
After 6 years of follow-up:
  • 5-year biochemical disease-free survival (bDFS) was 92% for those that received the SIB and 85% for those who didn't, a significant difference.
  • Both biochemical failures and clinical recurrences were cut in half by the SIB
  • In the limited follow-up period, there weren't enough distant metastases or deaths to detect a significant difference.
  • There were no significant differences in Grade 2 or Grade 3 urinary or rectal  toxicity,
  • As previously reported, late-term Grade 2 or greater toxicity was 10% for rectal, 27% for urinary with no significant differences.
  • There was no late-term Grade 3 rectal toxicity, and minimal late-term Grade 3 urinary toxicity in either arm.
  • There were no significant differences in patient-reported quality of life for urinary, rectal or sexual outcomes.
Because oncological results were as good as brachy boost therapy, the current gold standard for treating high-risk patients, and late-term urinary toxicity was minimal, hypofractionated IMRT with SIB is poised to become the new standard of care for high-risk patients. Longer follow-up will determine whether the results hold up.

There are some opportunities for improving results for patients even further.
  • SBRT with SIB: As we've seen extreme hypofractionation may provide more lasting results with equally good toxicity. Whole gland treatment with as high as 47.5 Gy in 5 fractions did not incur any excess toxicity in trials (see this link). 
  • Tumor detection and delineation with PSMA PET/CT scan: a small comparative study showed that PSMA PET/CT had superior sensitivity and positive predictive value compared to mpMRI. More importantly, it can eliminate patients who would not benefit from localized treatment because of occult metastases.
  • Genomics to detect radio-resistant tumors and radiation sensitivity
  • Imaging to detect hypoxic tumors (e.g., BOLD MRI, FAZA PET, or MISO PET)

Sunday, January 24, 2021

SBRT for High-Risk Patients

As we have seen, SBRT is a preferred therapy for low and intermediate-risk patients (see this link). It is effective, safe, convenient, and relatively inexpensive. However, its use for high-risk patients remains controversial.

Amar Kishan has accumulated data from 8 institutions that have used SBRT for 344 high-risk patients. They were treated as follows:

  • They received from 35 Gy-40 Gy in 5 treatments (7-8 Gy per treatment)
  • 72% received adjuvant ADT for a median of 9 months
  • 19% received elective nodal radiation

After a median follow-up of 49.5 months:

  • 4-year biochemical recurrence-free survival  (bRFS)was 82%
    • Higher dose, longer ADT, and nodal radiation were associated with better bRFS
  • 4-year metastasis-free survival was 89%
  • Late grade 3 GU toxicity was 2.3%
  • Late grade 3 GI toxicity was 0.9%
    • Toxicity was associated with dose and ADT use

Although the results of different prospective trials aren't comparable, the following table gives an idea of 4-6 year outcomes of prospective trials of high-risk patients using various therapies.





ADT (median)

Late GU Toxicity Grade ≥3

SBRT (1)

4 yrs


198-253 Gy

9 mos.


Surgery+SRT (2)

5 yrs


154 Gy

6 mos.

8% (3)

HDR-BT (4)

5 yrs


227-252 Gy

6.3 mos.


LDR- Brachy Boost (5)

5 yrs


227 Gy

12 mos.


HDR-Brachy Boost (6)

6 yrs


267 Gy

12 mos.


IMRT (7)

5 yrs


174 Gy

28 mos.


SBRT = stereotactic body radiation therapy,. External beam radiation (EBRT) concentrated in 5 treatments
bRFS= biochemical (PSA) recurrence-free survival
BED= biologically effective dose (comparable effectiveness)
ADT= androgen deprivation therapy used for a limited time to improve outcomes
late GU toxicity ≥3 = serious urinary side effects requiring intervention, occurring more than 3 months after therapy
HDR-BT = high dose rate brachytherapy (temporary implants)
LDR-BT = low dose rate brachytherapy (permanent implants/seeds)
Brachy Boost therapy - External beam radiotherapy (EBRT) with a boost of radiation to the prostate using brachytherapy 
IMRT = intensity-modulated radiation therapy, usually given in about 40 treatments

(2) with GS 8

As we've seen (see this link), brachy boost therapy is the gold standard for long-term recurrence-free survival. At about 5 years, however, all therapies seem to be about equally effective, with biochemical recurrence-free survival in the range of 78-91%. However, they differ markedly in the incidence of serious late-term urinary side effects. For LDR Brachy Boost therapy, the risk of urinary retention is high, while the risk of incontinence and urinary retention is elevated among patients having salvage radiation (SRT). External beam monotherapy, using either IMRT or SBRT, had a low risk of serious late-term urinary side effects (and almost no risk of serious rectal side effects).

IMRT, as a primary therapy for high-risk patients, requires long-term use of ADT to be effective. The DART RADAR trial showed that for high-risk patients, 6 months of adjuvant ADT wasn't nearly enough. Nabid suggests that 18 months of adjuvant ADT may be optimal when paired with IMRT. SBRT seems to be equally effective with less adjuvant ADT, but the optimal duration is yet to be determined.

The question that will only be resolved with longer follow-up is whether the recurrence rates are stable after 4 years, or whether they will deteriorate with longer follow-up. In the ASCENDE-RT trial of brachy boost therapy vs external beam radiation only, biochemical recurrence rates were similar after 5 years. Recurrence increased at a rate of 5% per year among those treated with EBRT alone, but only at a rate of 1% per year if they got the brachy boost. There was similar stability of outcomes when HDR brachytherapy was used. Recurrence after salvage radiation increased from 22% at 5 years to 30% at 10 years. There is every reason to believe that SBRT, which uses biologically effective doses (BED) of radiation similar to brachy boost therapy, will follow a stable recurrence pattern over time, but that remains to be shown.

Ensuring the safety of patients is critical, and high-risk patients are usually treated with wider margins that can affect toxicity. As we saw, SBRT there are many factors that must be considered when giving radiation this intense (see this link).

The first randomized trial (see this link) of radiation delivered in 6 treatments compared to 39 treatments to intermediate to high-risk patients proved that the cancer control and toxicity were similar. Another randomized trial (PACE-B) has already shown that the toxicity is lower with SBRT. An ongoing arm of that trial (PACE-C) is focusing on high-risk patients.

NCCN has included SBRT as a reasonable standard-of-care option for high-risk patients (Table 1 Principles of Radiation Therapy PROS-E 3 of 5 in NCCN Physicians Guidelines 3.2020). Due to the pandemic, an international panel of radiation oncologists is recommending that high-risk patients consider its use (see this link).

Saturday, May 25, 2019

Is whole pelvic radiation needed for primary treatment of Gleason 9/10?

Whether whole pelvic radiation therapy (WPRT) is beneficial for men newly diagnosed with Gleason 9/10 (Grade Group 5) is controversial. There is an ongoing randomized clinical trial (RTOG 0924) that will have results by 2027 at the earliest, but it includes intermediate and high-risk patients, very few of whom will have Gleason 9/10. Two previous randomized clinical trials (RCTs) gave conflicting results: RTOG 9413 showed a benefit to WPRT combined with ADT started before and continued through radiation treatment, while GETUG 01 found no benefit. However, neither RCT delivered doses of radiation that would be considered adequate by today's standards (70 Gy vs 80 Gy).

Sandler et al. analyzed the databases of 12 major institutions that treated 1170 Gleason 9/10 patients between 2000 and 2013.

  • 299 received external beam radiation therapy (EBRT) boost to the prostate + WPRT
  • 435 received EBRT only to the prostate + a small margin around it
  • 320  received a brachytherapy boost (BBT) to the prostate + WPRT
  • 116 received BBT only to the prostate + a small margin around it
  • Patients were matched on age, T stage, PSA, Gleason score, and analyzed by ADT duration

After median follow-up of 5.6 years, 5-year biochemical recurrence-free survival (bRFS) was:

  • 88% for BBT+WPRT
  • 78% for BBT alone
  • 66% for EBRT+WPRT
  • 58% for EBRT alone
  • WPRT was significantly improved by BBT (Hazard Ratio = 0.5, p=0.02) but not by EBRT (HR=0.8, p=0.4))
  • Neither distant metastasis-free survival nor prostate cancer-specific survival were significantly improved by WPRT

In interpreting these findings, patients should discuss the following considerations with their radiation oncologists.

Lack of long-term follow-up

As we have observed before (see this link), it can take 15 or more years until over half of high risk patients have detectable metastases (by bone scan/CT) or have succumbed to prostate cancer. In this study, only 35% of those getting EBRT alone had been diagnosed with distant metastases, and only 23% had died of prostate cancer. The rates for all other groups were smaller. As the data mature, we expect that the now-evident and statistically significant differences in biochemical failure will eventually result in higher rates of metastases and mortality.

Lack of local control with EBRT only

ASCENDE-RT proved that prostate cancer is better controlled in high-risk patients by a brachytherapy boost than by EBRT alone. Local control (of cancer in the prostate) is obviously required because the high grade cancer easily progresses and metastasizes from the prostate.

Lack of regional control with surgery

As we have seen, prostatectomy, even when followed by radiation (see this link) seems to provide inferior cancer control compared to BBT with WPRT. This may be because the salvage radiation dose to the prostate bed (usually only 66-70 Gy) is inadequate compared to the primary radiation dose (see this link).

Inadequate coverage/detection of pelvic lymph nodes

In the present study, patients received WPRT to the standard pelvic lymph nodes. We have seen that this is inadequate to reach  the cancerous pelvic lymph nodes in over 40% of patients (see this link). Current methods do not allow us to find most of the cancerous lymph nodes (see this link). While PET scans are not yet FDA-approved for high-risk patients (as they are for recurrent patients), there are a few available in clinical trials.

Inadequate dose to pelvic lymph nodes

The dose to pelvic lymph nodes is often about 45-50 Gy given in 1.8 Gy increments. If it's true that perfect cancer control is achieved only with doses around 80 Gy, this treatment may be inadequate to control some of the larger lymph node metastases. This may be especially true because lymph node metastases are not well-oxygenated (hypoxic). As PET/CTs and PET/MRIs become available for high-risk patients, it may become possible to target known lymph node metastases with higher doses. Another fertile area for investigative research is radiosensitization with hyperthermia (see this link).


In RTOG 0534, late Grade 2 or worse gastrointestinal toxicity occurred in 7% of those receiving WPRT. While this is higher than the 2% experiencing this degree of toxicity with prostate-only EBRT treatment, it is nevertheless at a low level. In a large non-randomized, retrospective study comparing WPRT to prostate-only radiation, Parry et al. found no difference in the 3-year cumulative incidence of gastrointestinal and urinary toxicity among high risk and locally advanced patients.

Because we may never have more reliable data, patients and their radiation oncologists must make this decision based on this study and judgement for the foreseeable future.

note: Thanks to Amar Kishan for allowing me to see the full text.

Thursday, March 8, 2018

Brachy boost therapy and surgery extend survival about the same in high risk patients, but brachy boost does more

Two retrospective studies were published in the last week, and they had some similar findings, but some dissimilar things to say about which treatment is best for high risk prostate cancer. The three therapies they looked at were the combination of brachytherapy and external beam radiation (brachy boost therapy - BBT), external beam therapy alone (EBRT), and surgery (RP).

Kishan et al. reported on 1,809 men with Gleason score of 9 or 10 who were treated between 2000 and 2013 at 12 tertiary cancer care institutions (UCLA, Los Angeles VA, California Endocurie Therapy Center, Fox Chase, Mt. Sinai, Cleveland Clinic, Wheeling Jesuit University, University of Michigan, Johns Hopkins, Oslo University, William Beaumont Hospital, and Dana-Farber).

Patient characteristics:
  • 639 were treated with radical prostatectomy (RP).
  • 734 were treated with EBRT only.
  • 436 were treated with BBT (BT was either low dose rate in 62% or high dose rate in 38%).
  • All patients were Gleason 9 or 10 on biopsy.
  • Pelvic LN involvement was discovered in 17% of RP patients ; 40% had positive surgical margins.
  • RP patients were younger (61 years of age) compared to EBRT or BBT patients (68 years of age)
  • RP patients were lower stage ( 87% clinical stage T1/T2) compared to EBRT (70% clinical stage T1/T2 ) or BBT patients (79% clinical stage T1/T2)
  • RP patients had lower pre-therapy PSA (7 ng/ml) compared to EBRT or BBT patients (10 ng/ml)
  • RP patients had lower percentage of Gleason score 10 (4%) compared to EBRT (6%) or BBT patients (9%)
Treatment specs
  • Among the RP patients, 43% had adjuvant or salvage radiation therapy (68 Gy).
  • Among radiation patients, about 90% had adjuvant ADT
  • Median dose of EBRT was 74 Gy.
    • adjuvant ADT continued for 22 months, median.
  • Median equivalent dose of EBRT+BT was 92 Gy
    • adjuvant ADT continued for 12 months.
Oncological outcomes

After a median follow-up of 4.2, 5.1 and 6.3 years for RP, EBRT, and BBT, respectively, the oncological outcomes (adjusted for age and disease characteristics) were as follows:
  • The 10-year rates of distant metastases were
    • 46% for RP 
    • 44% for EBRT
    • 13% for BBT
    • Differences between BBT and the two others were statistically significant.

  • The 10-year rates of prostate cancer-specific mortality (PCSM) were
    • 23% for RP
    • 26% for EBRT
    • 13% for EBRT + BT
    • Differences between BBT and the two others were statistically significant.

  • The 10-year rates of all-cause mortality (ACM) were
    • 32% for RP
    • 39% for EBRT
    • 31% for BBT
    • None of the differences were statistically significant.
    • There was a difference at 7.5 years in favor of BBT that vanished by 10 years.
In additional analyses, the authors looked at outcomes by duration of androgen deprivation for those receiving any kind of radiation. They found that ADT duration made no significant difference in detected metastases or PCSM within EBRT or BBT, and did not account for the difference between them. They also looked at radiation doses. EBRT patients who received <70 Gy had PCSM significantly worse than those who received ≥ 78 Gy. The rates of metastases did not differ. Notably, very few (11%) of the EBRT patients had both ≥ 78 Gy and ≥2 years of ADT, a combination that is now considered standard of care. Those that did had superior outcomes compared to RP. The use of LDR-BT or HDR-BT as part of BBT made no difference.

The authors conclude:
Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer–specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

In an analysis of the National Cancer Database, Ennis et al. reported on the overall survival of patients who were treated with RP, EBRT, and BBT for high-risk PC from 2004 to 2013. The database covers about 70% of all new prostate cancer patients treated in the US. The patient profile was:

  • 24,688 patients treated with RP, at least at first
  • 15,435 patients treated with EBRT
  • 2,642 patients treated with BBT.
  • All EBRT patients also had adjuvant ADT
  • BBT patients may or may not have had ADT
  • All were high risk by the NCCN definition: Either Gleason score 8-10, stage T3/4, or PSA≥20 ng/ml
  • RP patients were younger (62 years of age) compared to EBRT (70 years of age) or BBT patients (67 years of age)
  • RP patients were lower stage ( 89% clinical stage T1/T2) compared to EBRT (84% clinical stage T1/T2 ) or BBT patients (85% clinical stage T1/T2)
  • RP patients had lower pre-therapy mean PSA (19 ng/ml) compared to EBRT (23 ng/ml) but the same as BBT patients (19 ng/ml)
  • RP patients had lower percentage of Gleason score 8-10 (70%) compared to EBRT (78%) or BBT patients (73%)
  • Comorbidities were similar among groups.
  • The above risk factors as well as socioeconomic factors and year of diagnosis were used to adjust the raw data.
  • It is unknown what percent of RP patients had adjuvant or salvage radiation.
  • There was no data available on post-reatment metastases or prostate cancer-specific survival
Because surgery is sometimes aborted when pelvic LN cancer is discovered, they estimated the probability that patients had positive nodes, and included it as a risk factor. This would seem to double count those risk factors, but the authors say it had little effect. Based on their model, they estimated that the percent who had positive nodes was 10% of RP patients, 34% of EBRT patients, and 23% of BBT patients.

After a median follow-up of 36 months, the relative oncological outcomes (adjusted for age and other patient and disease characteristics), expressed as hazard ratios were as follows:

  • RP: 1.0
  • EBRT: 1.53 (i.e., 53% worse survival vs. RP)
    • EBRT with < 79.2 Gy: 1.68
    • EBRT with ≥79.2 Gy: 1.33
  • BBT: 1.17 (not significantly different from RP)
    • not different if ADT included
    • no interaction between comorbidities and treatment effects
The authors conclude:
This analysis showed no statistical difference in survival between patients treated with RP versus EBRT plus brachytherapy with or without AD. EBRT plus AD was associated with lower survival. 
In an accompanying editorial, Ronald Chen discusses the problem of drawing conclusions about comparative effectiveness from this kind of registry data in the absence of clinical trial data. He points out that patient selection criteria are not completely reflected in comorbidity data. He believes that those who are selected for EBRT are just less healthy than those who can undergo anesthesia for surgery or brachytherapy. Other unmeasured confounders include burden of disease, and patient and physician preferences.

The two studies had similar conclusions, but tell us different things. They both found no effect of treatment on overall survival. Lest one walk away thinking it then doesn't matter, the experience of living with painful, crippling metastases and the experience of dying from prostate cancer are horrific in themselves. In the Kishan study among top institutions, there is greater confidence than in many studies that deaths due to prostate cancer could be distinguished from death from other causes. Still, overall survival is impaired in patients with cancer, even if the cancer itself isn't the ultimate cause of death.

Although several randomized clinical trials (RCTs) have demonstrated significant improvements in progression-free survival from BBT compared to EBRT, none have yet demonstrated improvements in overall survival. We saw this recently in the 2005 Sathya RCT. But the prostate cancer-specific mortality advantage of BBT has been confirmed in another study. In a recent analysis of the SEER database, PCSM was 40% higher among patients who had EBRT compared to those who had BBT.

Other than the lack of metastasis data and PCSM in the NCDB, there were other important differences between the two studies. In the Ennis study, only 25%-35% were gleason 9 or 10, whereas all were in the Kishan study. Other differences included the lack of comorbidity data in the Kishan study, and the lack of adjuvant/salvage radiation data in the Ennis study.

Prostate cancer-specific mortality rates were cut in half by BBT, and metastases were only a fraction compared to the other treatments. While this does not prove causality (only a randomized clinical trial can do that), it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high risk patients may have to forgo brachy boost therapy in favor of high dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy will probably be the best choice. Patients who are treated with EBRT only, should receive a radiation dose of at least 79.2 Gy and two years of adjuvant ADT.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

- with thanks to Amar Kishan for allowing me to see the full text.

Wednesday, December 27, 2017

Is ADT still needed for high risk patients receiving brachy boost therapy?

Brachy boost therapy (external beam plus a brachytherapy boost to the prostate) is the gold standard for high risk patients, reporting the best oncological outcomes of any therapy. While long-term adjuvant ADT has proven to be beneficial in prolonging survival in high risk patients when used in conjunction with dose-escalated external beam radiation (DART 01/05 GICOR), there has never been a randomized trial to determine if there is any benefit to ADT when used with brachy boost therapy.

All we have to go by are several single or multi-institutional studies and one large database analysis. Almost all of the studies so far show no effect to short-term (4 months, starting 2 months prior and running concurrent with the radiation therapy) adjuvant ADT.

Two of the studies used a boost of low dose rate brachytherapy, predominantly using Pd-103 seeds. Dattoli et al.  found there was no significant difference in 16-year PSA progression-free survival (PSA-PFS) whether 4 months of ADT were added or not. D'Amico et al. also found no significant difference in 8-year prostate cancer specific mortality (PCSM) with the addition of ADT. However, they felt that it was "approaching significance" (p=.08) and might become statistically significant with longer follow-up. In contrast to the Dattoli study, the D'Amico study did not treat the pelvic lymph nodes.

A recent analysis of the large National Cancer Database by Yang et al. did not detect any benefit to adding ADT on 8-year overall survival (OS). The database lacks specific information about type of brachytherapy, radiation doses, duration of ADT, and whole-pelvic treatment,

Several studies that used high dose rate brachytherapy as a boost also looked at this issue retrospectively. Demanes et al. was the earliest of those studies. They found no difference in 10-year PSA-PFS in their 113 high risk patients treated between 1991-1998. Several subsequent studies confirmed those findings. Galalae et al. concatenated the databases from 3 institutions: Kiel University, University of Washington Seattle and William Beaumont Hospital. Short-term adjuvant ADT failed to demonstrate improved 10-year PSA-PFS in the 359 high risk patients treated between 1986 and 2000. And the lack of effect was demonstrated at all three institutions. Kotecha et al. also failed to find any differential improvement in 5-year PSA-PFS among 61 high risk patients treated with HDR brachy boost at Memorial Sloan Kettering between 1998 and 2009.

There has been one "outlier" study. Schiffmann et al. reported on 211 consecutive high-risk patients treated at the University Medical Center Hamburg-Eppendorf from 1999 to 2009. After 10 years, the biochemical recurrence-free survival was 50% with the adjuvant ADT but only 39% without it - a very statistically significant and meaningful difference. However, even the "improved" outcome seems low compared to the ASCENDE-RT trial where everyone got early neoadjuvant and adjuvant ADT. In that trial, the 9-year PSA-RFS for high risk patients receiving the trimodality therapy was 83%. Another multi-institutional study of HDR-brachy boost therapy reported 10-year PSA PFS of 85% with ADT and 81% without ADT in high risk patients. It is plausible that the patients in the Hamburg study had more advanced disease and had more undetected micrometastases compared to the other studies.

The following table summarizes the treatments given in the aforementioned studies, and whether there was a statistically significant improvement (p<.05).

Relative BED is the biologically effective radiation dose as a percent of the BED of 79.4 Gy of IMRT in 44 fractions.

Short-term vs. Long-term Adjuvant ADT

ADT is believed to have two effects when used in conjunction with radiation. Used before radiation begins (neoadjuvant use) and during radiation treatments (concurrent use), it radio-sensitizes the cancer. Lab findings suggest that it interferes with cancer cell repair of the induced DNA double-strand breaks. Used after radiation (adjuvant use), ADT is believed to "clean up" any remaining local micrometastases that survived. The death of cancer cells from both the radiation and the ADT dumps antigens into the serum that may activate T-cells. Those T-cells may hunt out and destroy small amounts of cancer cells nearby (the bystander effect) or systemically (the abscopal effect).

The bulk of the above retrospective studies suggest that the radiosensitizing effect is unnecessary with the very high radiation doses given with brachy boost therapy. However, what remains to be shown is whether long-term ADT might confer any additional benefit. The DART 01/05 GICOR trial proved that there was a significant benefit to 28 months of ADT compared to 4 months in high risk patients treated with dose-escalated EBRT. It is possible that while short-term ADT may have no benefit, long-term ADT combined with brachy boost therapy might.

TROG 03.04 RADAR was an Australian randomized trial that was designed to detect whether Zometa and longer duration of ADT (18 months vs 6 months) could provide better cures when combined with varying doses of radiation (radiation dose received was stratified but not randomized). Some of the patients received brachy boost therapy. In general, it found that higher radiation doses combined with longer duration of ADT provided the best outcomes. However, among those patients who received HDR brachy boost therapy, there was no significant difference in local progression (fig.2 - showing overlapping standard error bars) whether they received 18 months or 6 months of ADT. Future follow-up may reveal whether long-term ADT prevents distant progression.

The very high rates of cancer control (around 80%-85%) using brachy boost therapy may be as high as we can reasonably hope for, given that there will always be some patients with undetected occult micrometastases.

Better patient selection

High-risk patients are usually given a bone scan and CT to help rule out distant metastases. Bone scans are non-specific to prostate cancer and are not very sensitive when the PSA is below 20 ng/ml. CT scans detect metastases larger than about 1.2 cm, but most metastases are smaller than that. The newly-approved Axumin PET scan, and the experimental PSMA-based PET scans now in clinical trials may be able to detect those distant metastases earlier. However, there are currently no PET scans approved for high-risk patients outside of clinical trials (they are only approved for recurrent and advanced cancer patients). In the future, those high-risk men in whom metastases have been detected via PET scans may be better candidates for systemic therapies, while those in whom no metastases have been detected may be better candidates for brachy boost therapy. It may be economically justifiable to use PET scans for this purpose. Perhaps we will see another 5-10% increase in cancer control rates, even without ADT, with better patient selection. A recent analysis of recurrent patients after prostatectomy diagnosed using the Ga-68-PSMA PET/CT found that 12% had previously undetected metastases outside of the radiation treatment field.

Dose Escalation

At the high biologically effective doses (BEDs) used in all the brachy boost studies, there does not seem to be a significant interaction between dose used and whether ADT was effective. The Dattoli study had the lowest BED, but no benefit to added ADT, while the Galalae study had the highest BED, but also no benefit to added ADT. The Hamburg study had high BED but did demonstrate a benefit to added ADT. All of the brachy boost studies seem to have adequate radiation doses.

Whole Pelvic Radiation

It is possible that pelvic lymph nodes are best treated with a combination of radiation and ADT.  Bittner et al. looked at 186 high risk patients treated with the brachy boost  therapy. The 10-year PSA-PFS was:

  • 94% if they received both whole pelvic radiation and ADT
  • 82% if the received whole pelvic radiation without ADT
  • 90% if they received ADT without whole pelvic radiation
  • 75% if they received neither ADT nor whole pelvic radiation

ADT seemed to have a bigger effect than whole pelvic radiation. This may be because the whole pelvic radiation dose is inadequate. The doses given to the pelvic lymph nodes are quite a bit lower (about 50 Gy in 28 fractions) than the dose to the prostate. If Dr. King is right that prostate cancer is inherently radioresistant and requires a higher lethal dose (about 79.2 Gy/44 fx) to be effective, even when the cancer is only in the prostate bed (see this link), it is possible that pelvic lymph nodes require a higher dose as well. Because of the potential bowel toxicity of escalated pelvic doses, adjuvant ADT may be necessary to achieve effective cell kill rates without dose-limiting toxicity. We saw in a recent analysis that, in the salvage situation among patients with GS 8-10, whole pelvic radiation and ADT both had significant benefits. Whether whole pelvic radiation is effective in high risk patients treated with brachy boost therapy and ADT is the subject of a major ongoing randomized clinical trial (RTOG 0924).

Retrospective vs Prospective Trials

All of the published studies so far have been retrospective and are therefore subject to selection bias: those who received the ADT had more progressed disease than those who received the brachy boost without ADT. Therefore, it will always be impossible to convincingly resolve this issue without a prospective randomized clinical trial.

Patient decisions

Until we have definitive results from randomized clinical trials, the decision over whether to add ADT to brachy boost therapy will be challenging. Many patients are persuaded by the extra insurance ADT provides, and that only a short course seems to be necessary. Others are so ADT-averse that even a short course is unthinkable, especially with no concrete evidence of efficacy.

The decision over whether to include the whole pelvic area in the external beam radiation field may be an easier decision. High risk patients have a significant probability that there are small metastases harbored in pelvic lymph nodes. Recent studies have shown the treatment field must be wider than  was previously thought. For some patients with anatomical abnormalities, low visceral fat, and a history of bowel disease, this too may present a challenging decision.

Monday, March 27, 2017

Conflicting messages after surgery for high-risk patients from radiation oncologists and urologists

In spite of the data suggesting that brachy boost has better outcomes for high risk patients, it is being utilized less often and surgery is being utilized more often. After surgery, the high-risk patient is monitored by his urologist (Uro). If the urologist fears a recurrence, he may (1) refer his patient to a radiation oncologist (RO) for adjuvant or salvage radiation therapy (A/SRT), (2) refer his patient to a medical oncologist if he believes the recurrence is metastatic and incurable, or (3) he may continue to monitor the patient. The rate of utilization of A/SRT has been dwindling in spite of three major randomized clinical trials that proved that ART has better outcomes than waiting. If the patient does get to see a radiation oncologist, he may be advised to be treated soon, in conflict with the urologist advising him to wait. This puts the patient in a difficult situation.

Kishan et al. report the results of a survey among 846 ROs and 407 Uros. The researchers sought their opinions about under which conditions they would offer a high-risk post-prostatectomy patient A/SRT. For the purposes of their survey, they defined "adjuvant RT" as radiation given before PSA has become detectable, and "salvage RT" as radiation given after PSA has become detectable. "Early salvage RT" means PSA is detectable but lower than 0.2 ng/ml.

The following table shows the percent of ROs and Uros who agreed with each survey question:

ART underutilized
ART overutilized
SRT underutilized
SRT overutilized

SRT when first PSA is detectable
ART when first PSA is undetectable
Early SRT when first PSA is undetectable
SRT when first PSA is undetectable

Recommend SRT if PSA is:

2+ consecutive rises

Recommend ART if pathology report is adverse:

Positive margin
Extraprostatic Extension (pT3a)
Seminal Vesicle Invasion(pT3b)
Local organ spread (pT4)
Pelvic lymph node (pN1)
Gleason score 8-10
Prefer SRT

Recommend adjuvant ADT with ART if:

Positive margin
Extraprostatic Extension (pT3a)
Seminal Vesicle Invasion(pT3b)
Local organ spread (pT4)
Pelvic lymph node (pN1)
Gleason score 8-10

Recommend whole pelvic A/SRT if:

Positive margin
GS 8-10
No role

In contrast to Uros, ROs are more likely to believe that both ART and SRT are underutilized. Uros believe that are used about right. ROs often see patients too late if they see them at all.

When the first PSA is detectable, both kinds of doctors would recommend SRT. When the first PSA is undetectable, 43% of ROs would recommend ART nonetheless, while only 16% of Uros would recommend ART.

Most of the ROs would treat when they see 2 consecutive rises in PSA, or if the PSA was detectable and under 0.2. Most (54%) Uros would wait until PSA was over 0.2.

Over half the ROs would recommend ART to high risk patients demonstrating any of several adverse pathological features: positive margins, stage T3/4, or positive pelvic lymph nodes. The majority of Uros would not recommend ART to high risk patients with those adverse pathologies.

The majority (65%) of ROs would include adjuvant ADT if there were positive lymph nodes. Uros were less likely to recommend adjuvant ADT based on lymph node involvement and Gleason score.

While most of both groups would have added whole pelvic radiation for patients with positive lymph nodes, 82% of ROs would, but only 64% of Uros.

ROs, knowing that a locally advanced cancer can suddenly become metastatic, and therefore incurable, would like to give A/SRT as soon as possible. Uros, who treat patients for the combined effect of surgery and radiation on urinary and sexual function, would like to wait as long as possible. The patient is caught in the middle of this difficult decision. Some have recommended beginning neoadjuvant ADT at the lowest detectable PSA and extending that time for as long as needed  to give urinary tissues maximum time to heal. Whatever the high-risk patient may eventually decide is in his best interest, he should meet with an RO immediately after surgery to hear both sides of the issue. Uros are blocking access to information that the patient needs.